Anti-CD74 antibody-doxorubicin conjugate, IMMU-110, in a human multiple myeloma xenograft and in monkeys
Anti-CD74 antibody-doxorubicin conjugate, IMMU-110, in a human multiple myeloma xenograft and in monkeys
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DOI：
10.1158/1078-0432.ccr-05-0204
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发表时间：
2005-07-15
影响因子：
11.5
通讯作者：
Goldenberg, DM
中科院分区：
文献类型：
--
作者：
Sapra, P;Stein, R;Goldenberg, DM
目的：IMMU-110是一种药物免疫偶联物，由多柔比星与人源化抗CD 74单克隆抗体hLL 1偶联组成，多柔比星/单克隆抗体的比例类似于8：1（mol/mol）。CD 74是一种与HLA-DR相关的快速内化分子，其在几种肿瘤类型中具有高表达。在这里，我们描述了IMMU-110在小鼠和猴中的安全性评价以及在人多发性骨髓瘤细胞系MC/CAR.Experimental Design的异种移植模型中的功效研究：通过基于细胞的ELISA测定IMMU-110的体外结合，并用四唑测定法测定IMMU-110的细胞毒性。在无肿瘤BALB/c小鼠中检查放射性标记的IMMU-110的药代动力学和生物分布，并在携带MC/CAR细胞的严重联合免疫缺陷小鼠中评价治疗有效性。在CD 74阳性食蟹猴（Macaca fascicularis）中研究IMMU-110的急性毒性。结果：在体外，IMMU-110特异性结合CD 74并且对MC/CAR细胞具有细胞毒性。在体内，IMMU-110显示出与未缀合的hLL 1单克隆抗体相同的药代动力学和生物分布特征，除了较高的肾摄取。在注射多发性骨髓瘤细胞后5天，用低至50 μ g抗体/小鼠（或1.4 μ g多柔比星/小鼠）的单剂量IMMU-110治疗，导致大多数小鼠治愈。在小鼠中，在测试的最高蛋白质剂量（125 mg/kg）下没有观察到IMMU-110的宿主毒性。在食蟹猴中，在30和90 mg/kg dose.Conclusions观察到骨髓毒性：IMMU-110的优异的安全性和有效性特征支持这种免疫缀合物在治疗CD 74阳性B细胞恶性肿瘤中的临床测试。
Purpose: IMMU-110 is a drug immunoconjugate composed of doxorubicin conjugated to the humanized anti-CD74 monoclonal antibody, hLL1, at a doxorubicin/monoclonal antibody ratio of similar to 8:1 (mol/mol). CD74 is a rapidly internalizing molecule associated with HLA-DR, which has high expression by several tumor types. Here, we describe safety evaluations of IMMU-110 in mice and monkeys as well as efficacy studies in a xenograft model of the human multiple myeloma cell line, MC/CAR.Experimental Design: In vitro binding of IMMU-110 was determined by a cell-based ELISA and cytotoxicity of IMMU-110 assayed with a tetrazolium assay. Pharmacokinetics and biodistribution of radiolabeled IMMU-110 were examined in tumor-free BALB/c mice, and the therapeutic effectiveness was evaluated in severe combined immunodeficient mice bearing MC/CAR cells. Acute toxicity of IMMU-110 was studied in CD74-positive cynomolgus monkeys (Macaca fascicularis).Results: In vitro, IMMU-110 specifically binds to CD74 and is cytotoxic against MC/CAR cells. In vivo, IMMU-110 displayed a pharmacokinetic and biodistribution profile identical to that of unconjugated hLL1 monoclonal antibody, except for higher kidney uptake. Treatment with a single dose of IMMU-110 as low as 50 mu g antibody/mouse (or 1.4 mu g doxorubicin/mouse), 5 days post-injection of the multiple myeloma cells, resulted in cure of most mice. In mice, no host toxicity of IMMU-110 was observed at the highest protein dose tested (125 mg/kg). In cynomolgus monkeys, bone marrow toxicity was observed at 30 and 90 mg/kg doses.Conclusions: The excellent safety and efficacy profile of IMMU-110 supports clinical testing of this immunoconjugate in the treatment of CD74-positive B-cell malignancies.